Age-related cognitive decline (ARCD) is a complex convergent phenotype that prominenfiy involves impaired execufive funcfion (EF) likely through disrupfion of the dorsolateral prefrontal cortex (PFC) circuit; despite much speculafion, the cellular and molecular mechanisms that underiie this presumed disruption have not been demonstrated in humans. Cognifive impairment (Cl) or dementia (D) is highly prevalent among pafients with Parkinson's disease (PD) but remains an incompletely understood non- motor complication of this devastating illness. Indeed, many pafients with PD have neuropsychologically determined Cl, no demenfia (PD-CIND) at the time of inifial diagnosis. Like ARCD, patients with PD- CIND or PD-D display prominently impairment of EF; however, also like ARCD, the cellular and molecular bases are not clear. We hypothesize that selective regional- and neurotransmitter-specific degeneration in PFC or anterior neostriatum contributes significantly to impaired EF in ARCD, PD-CI, and PD-D. In Project 2 we will test our hypothesis through the following Specific Aims: (i) determine the magnitude and regional distribufion of dopamine (DA), norepinephrine (NE), and serotonin (5HT) degeneration in neocortex and neostriatum, and their associafions with cognitive function test results, from aged individuals without PD or demenfia but varying levels of ARCD, aged individuals with pathologic changes of PD but not a clinical diagnosis of PD and varying levels of Cl, and patients with closely related neurodegenerafive diseases, (ii) determine the magnitude, regional distribufion, and associations with cognifive test results of neostriatal medium spiny neuron spinodendritic degeneration in the same people whose fissue was invesfigated in Aim 1, and (iii) determine if selective loss of DA neurotransmission without neurodegenerafion leads to regionally restricted spinodendrific degenerafion in mice from Project 1. Complefion of these Specific Aims will provide the first integrated clinical, behavioral, morphometric, and neurochemical analysis of PFC and neostriatum in ARCD and PD with and without cognifive impairment, as well as in novel transgenic mice. This project is responsive to several points in the NIH Blueprint: it is a direct response to the therapeutic imperative for PD, it is highly translational as it will inform crifically neurolmaging and therapeufic efforts, and it draws on existing NIH funded resources. RELEVANCE (See instructions): This project will provide rafionale for new evidence-based intervenfions for cognifive impairment in PD beyond DA replacement strategies, including enhancing synaptic levels of other neurotransmitters, prevenfing death of selected neuron populafions, or ameliorafing the consequences of cell death.